Streszczenie

Wprowadzenie: Cytotoksyczność doksorubicyny (DOX) – leku przeciwnowotworowego, jest w głównej mierze wynikiem generowania reaktywnych form tlenu (RFT). Niektóre z enzymów ka­talizujących tę reakcję, a także enzymów obrony antyoksydacyjnej są regulowane przez hormony jodotyroninowe. W związku z tym zmiany w statusie hormonów jodotyroni­nowych mogą mieć wpływ na zaburzenia równowagi redoks oraz równowagi procesów anabolicznych i katabolicznych wywołane działaniem doksorubicyny. Celem badań była ocena wpływu skojarzonego podawania DOX i tyroksyny (T4) na morfologię wątroby, markery stresu oksydacyjnego i gospodarki lipidowej we krwi.
Metody: Szczury otrzymywały doksorubicynę dootrzewnowo (1,5 mg/kg m.c.) przez dziesięć tygo­dni, jeden raz w tygodniu. Jednocześnie podawano tyroksynę (0,2 lub 2,0 mg/l) w wodzie do picia przez czternaście tygodni.
Wyniki: We wszystkich grupach badanych zwierząt stwierdzono wyższy poziom malonylodialdehy­du (MDA). Jednocześnie u zwierząt, którym podawano DOX i T4 obserwowano mniejsze stężenie glutationu całkowitego w porównaniu do kontroli. Ocena morfologiczna wątroby nie wykazała oznak martwicy ani stłuszczenia. Stwierdzono natomiast zmniejszoną zawartość glikogenu w grupach DOX+T4 w porównaniu do grupy otrzymującej wyłącznie DOX. Rów­noczesne podawanie niższej dawki tyroksyny wraz z doksorubicyną wpłynęło na obniżenie stężenia triglicerydów (TG) oraz podwyższenie frakcji LDL cholesterolu.
Dyskusja: Suplementacja tyroksyny spowodowała zaburzenia równowagi redoks oraz stres oksyda­cyjny w wątrobie szczurów otrzymujących DOX. Badania wykazały normalizujący wpływ tyroksyny na obecność depozytów glikogenu, obserwowanych po podawaniu doksorubi­cyny. Poza niekorzystnym wpływem tyroksyny na poziom LDL u szczurów otrzymujących doksorubicynę, wykazano korzystne oddziaływanie mniejszej dawki tyroksyny na stężenie TG w surowicy.

Słowa kluczowe:doksorubicyna • hormony tarczycy • hepatotoksyczność • stres oksydacyjny • lipidy surowicy krwi

Summary

Introduction: Cytotoxicity of doxorubicin (DOX) – an anticancer drug, mostly results from reactive oxygen spe­cies (ROS) generation. Some enzymes catalyzing this process and enzymes of antioxidant defense are regulated by iodothyronine hormones. Thus, disorders in iodothyronine hormone status may affect doxorubicin-induced redox imbalance and anabolic/catabolic disorders. The aim of this study was to evaluate the influence of doxorubicin and thyroxine (T4) associated treatment on liver morphology, markers of oxidative stress and plasma lipid parameters.
Materials and methods: Rats were intraperitoneally treated with doxorubicin (1.5 mg/kg) once a week for ten weeks. Thyroxine was simultaneously given in drinking water (0.2 or 2.0 mg/l) for 14 weeks.
Results: There were higher hepatic level of malonyldialdehyde (MDA) of all tested groups and at the same time in rats treated with DOX plus T4 lower concentrations of total glutathione compared to controls were observed. Morphology of liver did not show any features of necrosis or steatosis but a decrease of glycogen content in T4+DOX groups compared to DOX treatment was ob­served. The concomitant administration of a lower dose of thyroxine and doxorubicin decreased triglycerides (TG) and increased LDL level compared to the DOX group.
Discussion: Thyroxin supplementation caused redox equilibrium disorders and oxidative stress in liver of rats receiving DOX. The study revealed the normalizing influence of thyroxin on glycogen deposits that were observed after doxorubicin treatment. Apart from an adverse impact of thyroxine administration on LDL in rats treated with doxorubicin, a beneficial effect of lower dose of thyroxine on serum TG level was revealed.

Key words:doxorubicin • thyroid hormones • hepatotoxicity • oxidative stress • serum lipids

Introduction

Doxorubicin is one of the most widely used cytostatics belonging to the anthracycline group, which is charac­terized by high antitumor efficacy. The main limitation of the drug therapy is its toxicity. In normal tissues, its mechanism is associated with the occurrence of oxidative stress [1,2,22]. The liver is an organ in which extensive metabolism of the drug takes place, leading to the forma­tion of not only more toxic metabolites, but also reactive oxygen species [3]. The associated redox changes can lead to anabolic/catabolic imbalances. On the other hand, io­dothyronine hormones synthesized by the thyroid gland are very important for maintaining such balance, partic­ularly in relation to lipids. There has been evidence that activation of the synthesis of free radicals is mediated by changes in the concentrations of thyroxine [7,17]. This suggests that these hormones may modify the organism’s response in the field of the oxidative stress mediated by doxorubicin, which implies changes in the lipid balance. Confirmation of these assumptions may have potential importance in clinical practice for hepatic changes in­duced by anthracyclines in individuals with disturbance of iodothyronine hormone balance. The aim of the study was to evaluate the impact of co-administration of doxo­rubicin and thyroxine on selected parameters of oxidative stress, liver morphology and serum lipid concentration.

Materials and Methods

Experimental model

The study was conducted on sexually mature albino rats of Wistar CRL: (WI)WUBR strain, obtained from a commercial breeder (Warsaw-Rembertow, Poland). The experimental protocol was approved by the Local Bioethical Committee of the Medical University of Lu­blin. The animals with the initial body weight of 160-195 g were maintained in stable conditions at 22°C with a 12-h light/dark cycle and given standardized granula­ted fodder LSM® (AGROPOL, Poland). The rats were intraperitoneally (i.p.) dosed with doxorubicin (DOX; Ebewe, Austria) while thyroxine (T4; Sigma-Aldrich, USA) was administered in drinking water. The animals were randomly divided into six groups (n=8): DOX – doxorubicin 1.5 mg/kg; 2T4+DOX – thyroxine 2.0 mg/l and doxorubicin 1.5 mg/kg; 0.2T4+DOX – thyroxine 0.2 mg/l and doxorubicin 1.5 mg/kg; 2T4 – thyroxine 2.0 mg/l; 0.2T4 – thyroxine 0.2 mg/l; and the untre­ated control group. Rats in groups DOX, 2T4+DOX and 0.2T4+DOX received doxorubicin (1.5 mg/kg) for 10 weeks (once a week). In addition, the animals from 2T4+DOX and 0.2T4+DOX groups received thyroxi­ne in drinking water at a concentration of 2.0 and 0.2 mg/l, respectively. The thyroxine administration started one week before the first dose of doxorubicin, and was completed three weeks after the last dose to exclude the presence of cytostatic at the time of obtaining tissue. The rats of groups 2T4 and 0.2T4 were i.p. treated with sali­ne and orally with thyroxine at the same concentrations (2.0 and 0.2 mg/l, respectively).

The animals were anesthetized with pentobarbital. Blood for biochemical studies was collected from the left ven­tricle to Vacuette tubes with clot activator. Two separate sections of the right liver lobe for histological and bio­chemical studies were collected to buffered formalin or sterile tubes, which were then frozen in liquid nitrogen and stored at -75°C. After thawing, the tissue sections were homogenized in 20 mM phosphate buffer at pH 7.4 at a ratio of 0.5 g of tissue in 2 cm3 of the buffer. A ho­mogenizer with a Teflon piston (Glas-col, USA) was used for homogenization (5 min at 4000 rpm). The obtained homogenates were centrifuged for 20 minutes at 14 000 rpm at 4°C.

Biochemical determinations

Serum free tetraiodothyronine (FT4) concentration was determined using a competitive ELISA test (No­vatec, Germany) according to the manufacturer’s man­ual based on the immune complex formed by the en­zyme-labeled antigen and final absorption reading at 450 nm with a microwell plate reader (BIO-TEK XS PowerWave, USA).

The evaluation of the lipid peroxidation product was based on malondialdehyde (MDA) concentration in hepatic homogenates. A commercial kit, TBARS (Cay­man, USA), was used for the assessment. The concept of the method is based on the reaction between MDA and thiobarbituric acid at 100°C and low pH. The con­centration of total glutathione (GSHT) was determined colorimetrically in the supernatants obtained from liver homogenates using the commercial set of reagents (Oxis­Research, USA).

Concentrations of total cholesterol (CHT), low density lipoprotein (LDL) and triglycerides (TG) were deter­mined colorimetrically using kits of reagents accord­ing to the manufacturer’s recommendations (Cormay, Poland).

Preparing for the assessment of histological preparations

4 µm histological slides obtained from paraffin blocks were routinely processed and stained with hematoxylin and eosin (H&E), as well as using periodic acid-Schiff method (paS) and paS after treatment with diastase (d-paS). Frozen tissue sections were stained with Sudan III. Histological specimens were evaluated by means of light microscopy.

Statistical Analysis

Materials and Methods

The obtained data were expressed as mean ± SD and analyzed using STATISTICA 5.0 software. Continuous data were compared among the experimental groups using the Kolmogorov-Smirnov test. The statistical sig­nificance of differences between control and the oth­er groups was evaluated either by Student’s t-test or Mann-Whitney U test and group-to-group compari­sons were assessed by one-way ANOVA and post-hoc Tukey’s HSD test. The value of p < 0.05 was considered statistically significant.

Results

The serum concentration level of free thyroxine (FT4) was significantly higher in animals treated with 2.0 mg of thyroxine than in the untreated control group (Table 1).

Table 1. Concentration (ng/l) of free thyroxine in rats’ serum

A significantly lower concentration of total glutathione in liver homogenates was found in rats receiving both doses of thyroxine concomitantly with doxorubicin. Interestingly, after applying only doxorubicin or a high­er dose of thyroxine alone, insignificant differences were observed while a lower concentration of thyrox­ine caused a significant increase in the total glutathione level. There were insignificant changes in GSHT level in groups of T4+DOX vs DOX. A significantly higher concentration of hepatic lipid peroxidation products (Table 2) was revealed in all groups of animals com­pared to the controls. However, insignificant changes of MDA concentration were found between T4+DOX and DOX groups.

Table 2. The concentration of GSH_T [nmol/g sample] and MDA [nmol/g sample] in the liver

After doxorubicin administration, the total cholesterol concentration in serum was significantly higher when compared to the control value (Table 3). These differ­ences in mean values compared to the control are inten­sified even more in animals that received doxorubicin in addition to thyroxine in both doses while differences in the concentrations of cholesterol among groups of T4+DOX versus DOX were not significant. In groups 0.2T4 and 2T4, the concentration of cholesterol was similar to the control. Doxorubicin administration did not significantly change LDL level when compared with the control group (Table 3). However, when doxorubi­cin was administered with T4 in both doses, the level of LDL was several fold higher compared to the control and DOX group.

Table 3. Total cholesterol (CHT), low density lipoproteins (LDL) and triglycerides (TG) [mmol/l] in serum

A higher concentration of triglycerides (TG) in serum (Table 3) was found in all groups receiving doxorubicin (DOX, 2T4+DOX and 0.2T4+DOX). In rats adminis­tered with doxorubicin with a higher dose of thyroxine the mean value of TG concentration was decreased com­pared to the group of DOX but the difference was not statistically significant. However, it was found that the lower dose of T4 significantly reduced serum TG level in rats receiving doxorubicin (0.2T4+DOX) compared to the group of DOX.

The liver of animals treated with doxorubicin presents he­patocytes with clear, granular cytoplasm. There were also hepatocytes with blurred boundaries focally seen, merging with each other (Fig. 1). A few clusters of mononuclear cells between the hepatocytes were also present, with no clear tendency to locate in certain areas of the lobules. On the slides stained with d-paS an increase in hepatic glycogen content in comparison with the control group was observed (Fig. 2). The hepatocytes in rats treated with doxorubicin simultaneously with thyroxine revealed gran­ular, eosinophilic cytoplasm with the appearance of par­enchymatous degeneration. Lack of changes in glycogen content was found when compared with the control. Hy­dropic degeneration was occasionally seen in the same he­patocytes of the periportal zone (Fig. 3). A few hepatocytes were observed with a more eosinophilic, homogeneous cytoplasm and pycnotic nuclei. In none of the studied groups were the features of steatosis or necrosis noted.

Figure 1. Hepatocytes with clear cytoplasm. Focal blurring of boundaries between hepatocytes. DOX group (H & E, mag. 200x; DOX group)

Figure 2. Deposits of glycogen in hepatocytes (paS , mag. 100x; DOX group)

Figure 3. Hepatocytes with granular, eosinophilic cytoplasm; mononuclear cell infiltration and sparse hepatocytes around triad with hydropic change (H & E, mag. 200x; 2T4+DOX group)

Discussion

The mechanism of the cytotoxic effect of doxorubicin in cancer cells is different from that in normal cells, in which the main mechanism – as outlined in the in­troduction – is associated with the generation of free radicals and consequent formation of oxidative stress [1,2,22]. The physiological dynamics of ROS formation changes in the imbalance of thyroxine levels [7,17]. It can be assumed that the effects caused by ROS gener­ated in the presence of doxorubicin will be different in individuals with iodothyronine hormone impairment. The common objective of the impact of doxorubicin and iodothyronine hormone on the synthesis of ROS is the mitochondria. The drug inhibits the first electron transport mitochondrial complex [22], and thyroxine, through its T2 metabolite, regulates the formation of ATP [4,15]. Any change in the rate of electron transport in the mitochondrial respiratory chain up-regulates ROS production [11,20]. However, while doxorubicin exerts only a peroxidative effect through the synthesis of ROS and the consumption of NADPH to their own bioac­tivation [22], iodothyronine hormones, apart from the peroxidative effect through the regulation of mitochon­drial function, also regulate the synthesis of the antioxi­dant NADPH, necessary for regeneration of glutathione. Thyroxine activates G6PDH and malic enzyme, which are the main source of cellular NADPH [6,23].

The study showed a decrease of total glutathione levels in the liver of rats treated with thyroxine (0.2 and 2.0 mg/l) with doxorubicin compared to controls, with no such changes in rats treated with doxorubicin alone. Based on the MDA level, oxidative stress was detected with similar intensity in all groups. The level of antioxidant enzyme was not tested because it does not give direct informa­tion about the severity of oxidative damage of molecules. The highest concentrations of cholesterol and LDL were demonstrated in the groups receiving doxorubicin with thyroxine. Thyroxine greatly elevated LDL levels in rats administered doxorubicin. The mean concentrations of TG in group 0.2T4+DOX were lower than in the group receiving DOX alone. The study showed no morphologi­cal features of necrosis or steatosis in any of the studied groups of animals, but showed a lower content of glyco­gen in the liver of rats treated with T4+DOX (0.2 and 2.0 mg/l) compared to rats treated with doxorubicin alone.

In the present study, the most severe changes associated with redox imbalance were observed in animals that re­ceived doxorubicin in addition to thyroxine. It is only in these groups that there were simultaneously reduced glutathione concentrations and an increase in the total lipid peroxidation, suggesting that the oxidative stress is a consequence of disturbances in the antioxidant system. The effect of lipid peroxidation may impair the integrity and permeability of the cell membrane, in extreme cases leading to necrosis. However, the lack of histological fea­tures of liver necrosis indicates that the observed increase in lipid peroxidation was not extremely high.

Milder changes in the redox system, however, may modu­late the dynamics of anabolic/catabolic processes, which appear as disorders of lipid and carbohydrate metabolism. A model example of such changes is alcoholic hyperlip­idemia followed by hepatic steatosis, as a result of the increase in the NADH/NAD ratio and caused by alco­hol metabolism. In this study, higher concentrations of cholesterol were observed in the T4+DOX groups and TG in the group 2T4+DOX. It should be assumed that these changes result from the activities of the administered chemotherapeutic agent. This is supported by the higher levels of both parameters in rats treated with doxorubicin only and with no differences in the groups of rats treated with thyroxine alone. In rats receiving both doses of thy­roxine with doxorubicin, on the other hand, the observed interactions in relation to LDL should be mainly assigned to thyroxine, since in animals treated with doxorubicin alone insignificantly higher levels of LDL were observed. In groups receiving the same doses of thyroxine the in­crease compared to control was significant but lower than in the T4+DOX groups. The results related to the effects induced by doxorubicin are confirmed in studies by other authors who revealed that receiving the drug frequently leads to the development of hyperlipidemia manifested as an increase in triglycerides, total cholesterol, LDL and phospholipid levels in serum [5,14,18,19]. The effect of thyroxine on lipid metabolism is multidirectional. Exami­nation of 4000 genes in the liver of mice with short- and long-term hypo- and hyperthyroidism revealed that tri­iodothyronine (the more active metabolite of thyroxine) controls the expression of many genes whose products are enzymes involved in lipogenesis, fat mobilization and activation of mitochondrial free fatty acid (FFA) oxida­tion [8]. The effect of thyroxine on lipid metabolism is observed in clinical practice. Hypothyroidism is accom­panied by an increase in blood lipids, whereas the admin­istration of thyroxine in patients with hypothyroidism leads to reduced lipid concentrations. Such activity was also observed in the current study since a significant de­crease of TG level was found in the 0.2T4+DOX group in comparison with the DOX group.

Taking into account the characteristics of doxorubicin, it may inhibit the activity of the respiratory chain in mito­chondria. Moreover, some previous studies demonstrat­ed inhibition of key mitochondrial enzymes by DOX, including complexes I and II, cytochrome oxidase and Fo/F1 ATP synthase [9,10,16]. The consequence of the complexes I and III inhibition chain is the increase of the synthesis of mitochondrial reactive oxygen species: O₂^{• –}, H₂O₂ and HO^• [16]. As mentioned in the present study, it was observed that the most serious changes associated with oxidative stress occurred in animals that received DOX with T4, and only in those groups was there a simultane­ous increase of lipid peroxidation and a decrease of the total glutathione level, which may indicate a disturbance in the antioxidant system. The respiratory chain inhibition by DOX should lead to a reduction of NADH oxidation. Furthermore, superoxide anion formed in the presence of DOX is a potent inhibitor of aconitase, and lipid peroxi­dation products – especially 4-hydroxy-2-nonenal (HNE) – inhibit the activity of α-ketoglutarate dehydrogenase [13,21]. It is also important that both enzymes take part in the cycle as well, and inhibition of its course leads to weakening of the synthesis of NADH [13,21]. The in­crease in the NADH/NAD ratio results in the weakening of the β-oxidation of fatty acids which are toxic to cells and must be neutralized. The increased synthesis of tri­glycerides can therefore occur in hepatocytes, which are then transported into the bloodstream in the form of very low density lipoprotein (VLDL). With significant inhibi­tion of β-oxidation, fatty acids are transformed to TG. As a result, TG may accumulate in cells. The assessment of liver histological features did not show steatosis. It seems that TG are effectively removed to the blood. This thesis may explain the cause of a higher blood TG concentration observed in rats treated with DOX.

It is possible that the redox imbalance in the liver of rats treated with doxorubicin will influence the balance of car­bohydrates. This supposition was confirmed based on paS and d-paS staining of sections obtained from the livers of animals treated exclusively with doxorubicin, where there was an increase in glycogen content. Interestingly, follow­ing co-treatment with DOX and thyroxine, no changes in glycogen amount were found. One reason for these dif­ferences may be an increase in glucose-6-phosphate dehy­drogenase – a pentose phosphate pathway enzyme, whose synthesis is up-regulated by thyroxine [8,12].

Thyroxine supplementation caused redox equilibrium dis­orders and oxidative stress in the liver of animals receiving doxorubicin, but these changes do not cause steatosis or necrosis. The study revealed the normalizing influence of thyroxine on glycogen deposits that were observed after doxorubicin treatment. A lower dose of thyroxine had a pos­itive impact on the serum triglyceride imbalance caused by doxorubicin. However, it has an adverse effect on the LDL cholesterol fraction in rats treated with doxorubicin.

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The authors have no potential conflicts of interest to declare.

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